Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-ls) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-l1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes.Ee Shan Pang, Ghazal Daraj, Katherine R. Balka, Dominic De Nardo, Christophe Macri, Hubertus Hochrein, Kelly-Anne Masterman, Peck S. Tan, Angus Shoppee, Zoe Magill, Nazneen Jahan, Mariam Bafit, Yifan Zhan, Benjamin T. Kile, Kate E. Lawlor, Kristen J. Radford, Mark D. Wright, and Meredith O, Keeff

Macroalgal meadow habitats support fish and fisheries in diverse tropical seascapes

Canopy-forming macroalgae can construct extensive meadow habitats in tropical seascapes occupied by fishes that span a diversity of taxa, life-history stages and ecological roles. Our synthesis assessed whether these tropical macroalgal habitats have unique fish assemblages, provide fish nurseries and support local fisheries. We also applied a meta-analysis of independent surveys across 23 tropical reef locations in 11 countries to examine how macroalgal canopy condition is related to the abundance of macroalgal-associated fishes. Over 627 fish species were documented in tropical macroalgal meadows, with 218 of these taxa exhibiting higher local abundance within this habitat (cf. nearby coral reef) during at least one life-history stage. Major overlap (40%–43%) in local fish species richness among macroalgal and seagrass or coral reef habitats suggest macroalgal meadows may provide an important habitat refuge. Moreover, the prominence of juvenile fishes suggests macroalgal meadows facilitate the triphasic life cycle of many fishes occupying diverse tropical seascapes. Correlations between macroalgal canopy structure and juvenile abundance suggests macroalgal habitat condition can influence levels of replenishment in tropical fish populations, including the majority of macroalgal-associated fishes that are targeted by commercial, subsistence or recreational fisheries. While many macroalgal-associated fishery species are of minor commercial value, their local importance for food and livelihood security can be substantial (e.g. up to 60% of landings in Kenyan reef fisheries). Given that macroalgal canopy condition can vary substantially with sea temperature, there is a high likelihood that climate change will impact macroalgal-associated fish and fisheries

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The state of Western Australia’s coral reefs

Western Australia’s coral reefs have largely escaped the chronic pressures affecting other reefs around the world, but are regularly affected by seasonal storms and cyclones, and increasingly by heat stress and coral bleaching. Reef systems north of 18°S have been impacted by heat stress and coral bleaching during strong El Niño phases and those further south during strong La Niña phases. Cumulative heat stress and the extent of bleaching throughout the northern reefs in 2016 were higher than at any other time on record. To assess the changing regime of disturbance to reef systems across Western Australia (WA), we linked their site-specific exposure to damaging waves and heat stress since 1990 with mean changes in coral cover. Since 2010, there has been a noticeable increase in heat stress and coral bleaching across WA. Over half the reef systems have been severely impacted by coral bleaching since 2010, which was further compounded by cyclones at some reefs. For most (75%) reef systems with long-term data (5–26 yrs), mean coral cover is currently at (or near) the lowest on record and a full recovery is unlikely if disturbances continue to intensify with climate change. However, some reefs have not yet experienced severe bleaching and their coral cover has remained relatively stable or increased in recent years. Additionally, within all reef systems the condition of communities and their exposure to disturbances varied spatially. Identifying the communities least susceptible to future disturbances and linking them through networks of protected areas, based on patterns of larval connectivity, are important research and management priorities in coming years while the causes of climate change are addressed

Alzheimer's disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci

10.1371/journal.pone.0148717PLoS ONE112e014871

Neutrinoless Double Beta Decay

International audienceThis White Paper, prepared for the Fundamental Symmetries, Neutrons, and Neutrinos Town Meeting related to the 2023 Nuclear Physics Long Range Plan, makes the case for double beta decay as a critical component of the future nuclear physics program. The major experimental collaborations and many theorists have endorsed this white paper